In the year 2000, an estimated 22 million people were suffering from cancer worldwide and 6.2 millions deaths were attributed to this class of diseases. Every year, there are over 10 million new cases and this estimate is expected to grow by 50% over the next 15 years (WHO, World Cancer Report. Bernard W. Stewart and Paul Kleihues, eds. IARC Press, Lyon, 2003). Current cancer treatments are limited to invasive surgery, radiation therapy and chemotherapy, all of which cause either potentially severe side-effects, non-specific toxicity and/or traumatizing changes to ones body image and/or quality of life. Cancer can become refractory to chemotherapy reducing further treatment options and likelihood of success. The prognosis for some cancer is worse than for others and some are almost always fatal. In addition, some cancers with a relatively high treatment success rate remain major killers due to their high incidence rates.
One of the causes for the inadequacy of current cancer treatments is their lack of selectivity for affected tissues and cells. Surgical resection always involves the removal of apparently normal tissue as a “safety margin” which can increase morbidity and risk of complications. It also always removes some of the healthy tissue that may be interspersed with tumor cells and that could potentially maintain or restore the function of the affected organ or tissue. Radiation and chemotherapy will kill or damage many normal cells due to their non-specific mode of action. This can result in serious side-effects such as severe nausea, weight loss and reduced stamina, loss of hair etc., as well as increasing the risk of developing secondary cancer later in life. Treatment with greater selectivity for cancer cells would leave normal cells unharmed thus improving outcome, side-effect profile and quality of life.
The selectivity of cancer treatment can be improved by targeting molecules that are specific to cancer cells and not found on normal cells. These molecules can then be used as a target to antibody-based diagnostic or therapeutics or for drugs capable of altering their function.
What little is known about the wild type Scratch protein, has been obtained on the basis of conceptual translation and analysis of the resulting hypothetical protein sequence. Expression of Mammalian Scratch (Scrt) mRNA has been found confined to the brain, spinal cord and newly differentiating, postmitotic neurons suggesting a potential role in neuronal differentiation. The human mammalian Scratch gene has been mapped to q24.3 (chromosome 8) Nakakura et al 2001a, PNAS vol 98 p 4010-4015 and Nakakura et al 2001. Mol. Brain. Res. Vol 95 p 162-166.
Mammalian Scratch shares a SNAG domain with other zinc finger proteins, such as SNAI1, SNAI2, SNAI3, GFII and GFIIB. While quite a few labs working on SNAG domains (Bathe E et al. 2000. Nat. Cell Biol, Vol. 2:84-89; Kataoka H et al., 2000. Nucleic Acids Res. Vol. 28:626-633; Grimes H L et al. 1996. Mol. Cell. Biol. Vol. 16:6263-6272; Hemavathy K et al. 2000. Mol. Cell. Biol. Vol: 20:5087-5095) and snail locomotor functionality have come across the over-expression of the Scrt gene, the presence of the protein itself has not been shown thus far. Based on the hypothetical protein sequence, the Scratch protein should have five zinc finger domains and a SNAG domain responsible for a function in transcription repression. The sequence indicates that the resulting protein would be an intra-nuclear one and in fact expression of recombinant Mammalian Scratch has been found confined to nucleus of transfected cells (Nakakura et al 2001a, PNAS vol 98 p 4010-4015).